Glucose Peaks and the Risk of Dementia and 20-Year Cognitive Decline

Abstract

Objective: Hemoglobin A_1c (HbA_1c), a measure of average blood glucose level, is associated with the risk of dementia and cognitive impairment. However, the role of glycemic variability or glucose excursions in this association is unclear. We examined the association of glucose peaks in midlife, as determined by the measurement of 1,5-anhydroglucitol (1,5-AG) level, with the risk of dementia and 20-year cognitive decline.

Research design and methods: Nearly 13,000 participants from the Atherosclerosis Risk in Communities (ARIC) study were examined. Dementia was ascertained from surveillance, neuropsychological testing, telephone calls with participants or their proxies, or death certificate dementia codes. Cognitive function was assessed using three neuropsychological tests at three visits over 20 years and was summarized as z scores. We used Cox and linear mixed-effects models. 1,5-AG level was dichotomized at 10 μg/mL and examined within clinical categories of HbA_1c.

Results: Over a median time of 21 years, dementia developed in 1,105 participants. Among persons with diabetes, each 5 μg/mL decrease in 1,5-AG increased the estimated risk of dementia by 16% (hazard ratio 1.16, P = 0.032). For cognitive decline among participants with diabetes and HbA_1c <7% (53 mmol/mol), those with glucose peaks had a 0.19 greater z score decline over 20 years (P = 0.162) compared with those without peaks. Among participants with diabetes and HbA_1c ≥7% (53 mmol/mol), those with glucose peaks had a 0.38 greater z score decline compared with persons without glucose peaks (P < 0.001). We found no significant associations in persons without diabetes.

Conclusions: Among participants with diabetes, glucose peaks are a risk factor for cognitive decline and dementia. Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention.

Figure 1

Adjusted HRs (95% CI) for the association of 1,5-AG with incident dementia among persons with diabetes. HRs were estimated using Cox proportional hazards regression among persons with diabetes (N = 1,659) with adjustment for age, race (black/white), sex, education, hypertension (yes/no), history of stroke (yes/no), history of coronary heart disease (yes/no), APOE4 genotype (0, 1, or 2 alleles), and HbA_1c. 1,5-AG was measured at baseline (1990–1992) and modeled continuously with the reference point of 1,5-AG set to the 60th percentile (∼10 μg/mL). We also modeled the association using linear splines with knots at the 5th, 35th, 65th, and 95th percentiles. Diabetes was defined as a self-reported physician diagnosis of diabetes, use of glucose-lowering medication, or an HbA_1c level of ≥6.5% (48 mmol/mol). The median follow-up time was 18 years, and there were 217 cases of incident dementia.

Figure 2

Estimated association between baseline categories of diabetes and 20-year cognitive decline by diabetes, HbA_1c, and 1,5-AG group. Estimates and 95% CIs are from linear mixed-effects models with adjustment for age, age squared, race–field center, sex, education, cigarette smoking status, drinking status, hypertension, history of stroke, history of coronary heart disease, APOE4 genotype, BMI, and interactions between these variables and time. Time since baseline (visit 2) was the time axis and was modeled with a linear spline with a knot at 6 years. A random intercept and two random slopes for time (one for each spline term) were included, and the three random effects were assumed to be independent. Slope: dashed lines indicate linear regression fit across the three diabetes groupings (no diabetes, diabetes HbA_1c <7%, diabetes HbA_1c ≥7%) and 1,5-AG category by creating an indicator that takes on the values 1, 2, or 3. Decline indicates the estimated 20-year cognitive decline per category. The P values comparing 1,5-AG concentrations ≥10 to <10 μg/mL are from analyses stratified by diabetes group (no diabetes, diabetes with HbA_1c <7%, diabetes with HbA_1c ≥7%) with additional adjustment for HbA_1c. An HbA_1c of 7% is equivalent to 53 mmol/mol.